ABSTRACT Substance use (SU) and substance use disorders (SUD) cause extensive morbidity and mortality but have been neglected historically by mainstream health care. The Health Systems Node joined the National Institute on Drug Abuse?s Clinical Trials Network (CTN) in 2015, led by Drs. Campbell, Weisner and Bradley, addiction research leaders in innovative implementation research and pragmatic trials in medical settings. Our node includes 16 Learning Health Systems with national representation and rich population diversity, and represents over 26 million patients. Our faculty are researchers who are embedded in their health systems and committed to cutting-edge addiction research. They bring multidisciplinary expertise in conducting research using innovative methods in different medical settings (e.g. primary care, addiction medicine, OB/GYN, psychiatry, rural communities), and with diverse populations (e.g. under-represented minorities, adolescents, pregnant women, patients with HIV). The node had an outstanding track record in its first 5 years leading 6 multi-site studies, including the CTN?s first entirely electronic health record (EHR)-based pragmatic implementation trial as well as participating in several studies led by other nodes. This renewal application builds upon that success to address the CTN?s objectives over the next 5 years through 3 broad Research Agendas: 1) To test approaches to increasing identification of SU and SUD, and engagement in treatment. For example, we propose a multisite implementation trial to test an innovative approach to implementing cannabis and other drug screening and assessment for SUD; 2) To test new approaches to improve SUD outcomes in medical settings. For example, we propose a point-of-care pragmatic effectiveness trial of telephonic nurse collaborative care and an efficacious smartphone-based SUD treatment, in patients with newly diagnosed SUD; and 3) To develop novel measures and methods for SUD research using EHRs. For example, we propose to validate a 7-item SU severity measure developed by the NIH Roadmap initiative Patient Reported Outcome Measurement Information System (PROMIS) for use in measurement-based care of SUD. These agendas emphasize population-based studies, including pragmatic randomized controlled trials, comparative effectiveness studies, and implementation research, and leverage EHRs. Public Health and Clinical Practice Impact. Over 14.9 million patients with untreated SUD have health care visits annually in the US. If 10% of these patients were identified, engaged and successfully treated, it would translate to 1.5 million patients with resolved SUD each year who otherwise would have gone untreated. The Health Systems Node faculty and infrastructure, in collaboration with the CTN, are uniquely positioned to conduct and disseminate research that advances the integration of SUD treatment into routine medical care, and ultimately to improve patient outcomes and public health.